Effects of Increasing Intracellular Reactive Iron Level on Cardiac Function and Oxidative Injury in the Isolated Rat Heart

Oubidar, Mohamed; Marie, Christine; Mossiat, Claude; Bralet, J

doi:10.1006/jmcc.1996.0166

Cited by 14 publications

(3 citation statements)

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“…In support of this hypothesis, in vitro [78,79] and in vivo [80] studies indicate that exposure of neuronal cells to iron induces a dose-dependent increase in lipid peroxidation leading to loss of cell viability through apoptosis [79]. Additionally, iron-induced free radical production and neurodegeneration were both attenuated by the iron chelator deferoxamine, in rat hippocampal neurons [81].…”

Section: Mechanism Of Iron Toxicitymentioning

confidence: 67%

Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

Gaasch,

Lockman,

Geldenhuys

et al. 2007

Neurochem Res

182

111

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Iron accumulation or iron overload in brain is commonly associated with neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, and also plays a role in cellular damage following hemorrhagic stroke and traumatic brain injury. Despite the brain's highly regulated system for iron utilization and metabolism, these disorders often present following disruptions within iron metabolic pathways. Such dysregulation allows saturation of proteins involved in iron transport and storage, and may cause an increase in free ferrous iron within brain leading to oxidative damage. Not only do astrocytes, neurons, and brain endothelial cells serve unique purposes within the brain, but their individual cell types are equipped with distinct protective mechanisms against iron-induced injury. This review evaluates iron metabolism within the brain under homeostatic and pathological conditions and focuses on the mechanism(s) of brain cellular iron toxicity and differential responses of astrocytes, neurons, and brain vascular endothelial cells to excessive free iron.

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Section: Mechanism Of Iron Toxicitymentioning

confidence: 67%

Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

Gaasch,

Lockman,

Geldenhuys

et al. 2007

Neurochem Res

182

111

View full text Add to dashboard Cite

show abstract

“…Given the role of free iron in the production of radical oxygen species (ROS), including superoxide anions and hydroxyl radicals (Minotti and Aust, 1992), and the damaging effect of these ROS in brain ischemia (Baker et al, 1998;Kim et al, 2001;Imai et al, 2003), iron chelators are of obvious interest as therapeutic agents in this pathology. Effective treatments, however, require an iron chelator capable of entering brain cells since the availability of free iron at critical intracellular space appears to be essential to the cellular damage caused by ROS (Lesnefsky and Ye, 1994;Oubidar et al, 1996). This may explain why histological data supporting a cytoprotective effect of deferoxamine (the most used iron chelator in clinical and experimental settings) in brain ischemia are lacking.…”

mentioning

confidence: 99%

Cytoprotective Efficacy and Mechanisms of the Liposoluble Iron Chelator 2,2′-Dipyridyl in the Rat Photothrombotic Ischemic Stroke Model

Demougeot¹,

Hoecke²,

Bertrand³

et al. 2004

J Pharmacol Exp Ther

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We examined the efficacy of the liposoluble iron chelator 2,2Ј-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1␣ (HIF-1␣) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (ϩ100%) and HIF-1␣ (Ϫ50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia.

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“…Thus, whereas a similar extracellular hydroxyl formation was observed after either liposoluble and hydrosoluble iron exposure, heart dysfunction was observed only after liposoluble iron treatment. [33] Similarly, in heart submitted to ischemia and reperfusion, application of deferoxamine (a hydrosoluble iron chelator) at the onset of reperfusion was reported to inhibit extracellular hydroxyl radical generation but not to attenuate myocardial injury. [34] This lack of relation between extracellular hydroxyl radical production and cell damage consecutive to iron injection or ischemia/ reperfusion indicates that increased dialysate DHBA level has to be only considered as an index of the presence of reactive iron outside the cells.…”

Section: Discussionmentioning

confidence: 98%

Effects of a Direct Injection of Liposoluble Iron into Rat Striatum. Importance of the Rate of Iron Delivery to Cells

Demougeot

Méthy

Prigent‐Tessier

et al. 2003

Free Radical Research

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For a better understanding of the role of iron imbalance in neuropathology, a liposoluble iron complex (ferric hydroxyquinoline, FHQ) was injected into striatum of rats. The effects of two modalities of iron injections on brain damage, hydroxyl radical (*OH) production (assessed by the salicylate method coupled to microdialysis) and tissue reactive iron level (evaluated ex vivo by the propensity of the injected structure for lipid peroxidation) were examined. Rapid injection of FHQ (10 nmoles of 5 mM FHQ pH 3 solution over 1-min period) but not that of corresponding vehicle led to extensive damage associated with increased tissue free iron level in the injected region. Conversely, neither lesion nor free iron accumulation was observed after slow FHQ injection (10 nmoles of a 100 microM FHQ pH 7 solution over 1-h period) as compared to corresponding vehicle injection. Production of *OH was induced by slow FHQ injection but not by rapid FHQ injection, probably as a result of in vivo abolition of iron-induced *OH formation by acid pH. Indeed, rapid injection of FAC pH 7 (ferric ammonium citrate, 5 mM in saline) was associated with *OH formation whereas rapid injection of FAC pH 3 did not. Our results identify the rate of iron delivery to cells as an important determinant of iron toxicity and do not support a major role for extracellular *OH in damage associated with intracerebral iron injection.

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Effects of Increasing Intracellular Reactive Iron Level on Cardiac Function and Oxidative Injury in the Isolated Rat Heart

Cited by 14 publications

References 0 publications

Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

Cytoprotective Efficacy and Mechanisms of the Liposoluble Iron Chelator 2,2′-Dipyridyl in the Rat Photothrombotic Ischemic Stroke Model

Effects of a Direct Injection of Liposoluble Iron into Rat Striatum. Importance of the Rate of Iron Delivery to Cells

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